TY - JOUR
T1 - Rett syndrome and beyond
T2 - Recurrent spontaneous and familial MECP2 mutations at CpG hotspots
AU - Wan, Mimi
AU - Lee, Stephen Sung Jae
AU - Zhang, Xianyu
AU - Houwink-Manville, Isa
AU - Song, Hae Ri
AU - Amir, Ruthie E.
AU - Budden, Sarojini
AU - Naidu, Sakku Bai
AU - Pereira, Jose Luiz P.
AU - Lo, Ivan F.M.
AU - Zoghbi, Huda Y.
AU - Schanen, N. Carolyn
AU - Francke, Uta
N1 - Funding Information:
We thank the families with RTT for their participation, B. Foellmer, V. Meyers, and R. F. Pilotto for technical contributions, S. Fulmer-Smentek for critical reading of the manuscript, and K. Redman for administrative assistance. We are grateful to the Genome Analysis Group at the Institute for Molecular Biotechnology in Jena, Germany, for depositing the genomic MECP2 sequence in the public database. This work was supported by the Howard Hughes Medical Institute (support to U.F., S.S.J.L., X.Z., and H.Y.Z.); by NIH grants HD24234 (to H.Y.Z., U.F., and M.W.), HD24448 and RR00052 (to S.N.), HD034610 (to N.C.S. and H.-R.S.), and HD01103 (to N.C.S); by a Lynn Marie Chandler Postdoctoral Fellowship (to M.W.) by the Research for Rett Syndrome Foundation (support to S.N.), and by the International Rett Syndrome Association (support to R.E.A. and I.H.-M).
PY - 1999
Y1 - 1999
N2 - Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X- inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.
AB - Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X- inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.
UR - http://www.scopus.com/inward/record.url?scp=0033365401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033365401&partnerID=8YFLogxK
U2 - 10.1086/302690
DO - 10.1086/302690
M3 - Article
C2 - 10577905
AN - SCOPUS:0033365401
SN - 0002-9297
VL - 65
SP - 1520
EP - 1529
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -